JP7427242B2 - Optically active azide ester and method for producing the same - Google Patents
Optically active azide ester and method for producing the same Download PDFInfo
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- -1 azide ester Chemical class 0.000 title claims description 30
- 238000004519 manufacturing process Methods 0.000 title description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Natural products C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 8
- IVRMZWNICZWHMI-UHFFFAOYSA-N Azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- OCVXZQOKBHXGRU-UHFFFAOYSA-N iodine(1+) Chemical compound [I+] OCVXZQOKBHXGRU-UHFFFAOYSA-N 0.000 claims 1
- 150000003751 zinc Chemical class 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 21
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 230000003287 optical effect Effects 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000011701 zinc Substances 0.000 description 7
- 229910052725 zinc Inorganic materials 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 238000011914 asymmetric synthesis Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N para-methoxy benzoic acid Natural products COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 101000652482 Homo sapiens TBC1 domain family member 8 Proteins 0.000 description 2
- 102100030302 TBC1 domain family member 8 Human genes 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- 150000001414 amino alcohols Chemical class 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- XYLMUPLGERFSHI-UHFFFAOYSA-N alpha-Methylstyrene Chemical compound CC(=C)C1=CC=CC=C1 XYLMUPLGERFSHI-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000006256 asymmetric dihydroxylation reaction Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000005657 iodolactonization reaction Methods 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 150000003463 sulfur Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000004246 zinc acetate Substances 0.000 description 1
Description
本発明は、光学活性アジドエステルおよびその製造方法に関する。 The present invention relates to an optically active azide ester and a method for producing the same.
糖やアミノ酸を基本構成単位とする生体高分子は、人間の体内で高度な不斉空間を構築しているため、この生体分子を受容体とする医薬品も光学活性を有している必要がある。このような光学活性な物質を合成する方法は不斉合成法と呼ばれており、不斉合成法の中でも少量の不斉源から理論上無限の光学活性体を合成することが可能な触媒的不斉合成法は極めて重要なものとなっている。 Biopolymers whose basic constituent units are sugars and amino acids have a highly asymmetric structure in the human body, so pharmaceuticals that use these biomolecules as receptors must also have optical activity. . This method of synthesizing optically active substances is called asymmetric synthesis, and among the asymmetric synthesis methods, there is a catalytic method that can theoretically synthesize an infinite number of optically active substances from a small amount of chiral source. Asymmetric synthesis methods have become extremely important.
アジド基は、還元によりアミンへ、またアルキンとの反応でトリアゾールに容易に変換できることから、医薬品の合成に有用な官能基である。とくに、隣り合った炭素上にアジド基とエステル等の酸素官能基（カルボキシル基という）を有する分子からはアミノアルコールの供給に繋がり、アジドに結合した炭素が不斉炭素の場合にはこれら化合物を光学活性体として供給する技術が必要となる。しかしながら、隣り合った炭素上にアジド基とカルボキシル基を有する分子の不斉合成の例はない。尚、従来の技術として、アジドオレフィンの不斉ジヒドロキシル化による光学活性アジドアルコールの合成例が下記非特許文献１に記載されている。一方で、不斉ハロゲン化を経る光学活性アジドエステルならびにアミノエステルへの分子変換法の例が下記非特許文献２に記載されている。
また、今回の発明に繋がった成果として、本発明者は、先に光学活性３，３’－アミノイミノビナフトール配位子と酢酸亜鉛からなる亜鉛三核錯体を開発し、分子内反応である触媒的不斉ヨードラクトン化反応を特許文献１ならびに非特許文献３、４に報告している。
Azide groups are useful functional groups in the synthesis of pharmaceuticals because they can be easily converted to amines by reduction and to triazoles by reaction with alkynes. In particular, molecules with an azide group and an oxygen functional group (called a carboxyl group) such as an ester on adjacent carbons lead to the supply of amino alcohol, and when the carbon bonded to the azide is an asymmetric carbon, these compounds are A technology to supply it as an optically active substance is required. However, there is no example of asymmetric synthesis of a molecule having an azide group and a carboxyl group on adjacent carbon atoms. As a conventional technique, an example of synthesis of an optically active azide alcohol by asymmetric dihydroxylation of an azide olefin is described in Non-Patent Document 1 below. On the other hand, an example of a method for converting molecules into optically active azide esters and amino esters through asymmetric halogenation is described in Non-Patent Document 2 below.
In addition, as a result that led to the present invention, the present inventors previously developed a zinc trinuclear complex consisting of an optically active 3,3'-aminoiminobinaphthol ligand and zinc acetate, and catalyzed an intramolecular reaction. The asymmetric iodolactonization reaction has been reported in Patent Document 1 and Non-Patent Documents 3 and 4.
本発明では、アジドエステルを不斉合成するにあたり、安価で入手容易なα-メチルスチレンなどの安価な試薬を原材料に設定し、分子間の触媒的不斉ヨードエステル化と、それに続くアジ化物イオンとの反応を行う。中間体のヨードエステルを高収率、高立体選択的に得る反応条件を確立する必要がある。更に、光学純度を損なうことなくアジドエステルへ変換するための反応条件を確立する必要がある。 In the present invention, in the asymmetric synthesis of azide esters, inexpensive reagents such as inexpensive and easily available α-methylstyrene are used as raw materials, and intermolecular catalytic asymmetric iodoesterification and subsequent azide ion Perform a reaction with. It is necessary to establish reaction conditions to obtain the intermediate iodoester in high yield and with high stereoselectivity. Furthermore, it is necessary to establish reaction conditions for conversion to an azide ester without compromising optical purity.
そこで、本発明は、上記課題を鑑み、スチレン化合物の触媒的不斉ヨードエステル化と続くアジ化物イオンとの反応を行い、新規な光学活性アジドエステル及びその製造方法を提供することを目的とする。 Therefore, in view of the above problems, the present invention aims to provide a novel optically active azide ester and a method for producing the same by performing catalytic asymmetric iodoesterification of a styrene compound and subsequent reaction with an azide ion. .
本発明者らは、上記課題について鋭意検討を行なっていたところ、３，３’－アミノイミノビナフトール配位子と亜鉛カルボキシレートからなる亜鉛二核錯体触媒の存在下、スチレン化合物とカルボン酸を反応させることで、光学活性ヨードエステルが得られることを見いだした。更に、得られた光学活性ヨードエステルに対しアジ化ナトリウムを作用させることで、光学純度を損なうことなく新規光学活性アジドエステルが得られる点を発見し、本発明を完成させるに至った。 The present inventors have been conducting intensive studies on the above-mentioned problem, and found that a styrene compound and a carboxylic acid are reacted in the presence of a zinc dinuclear complex catalyst consisting of a 3,3'-aminoiminobinaphthol ligand and a zinc carboxylate. It was discovered that an optically active iodoester can be obtained by doing this. Furthermore, the inventors discovered that a novel optically active azide ester can be obtained without impairing optical purity by allowing sodium azide to act on the obtained optically active iodoester, thereby completing the present invention.
即ち、光学活性ヨードエステルを製造する方法は、下記式（１）で示される３，３’－アミノイミノビナフトール配位子に対応する亜鉛カルボン酸塩を作用させて得られる亜鉛の二核錯体触媒の存在下で、スチレン化合物とカルボン酸を反応させて下記式（２）で示される光学活性ヨードエステルを不斉合成し、得られたヨードエステルとアジ化ナトリウムを反応させるものである。 That is, the method for producing an optically active iodoester uses a zinc dinuclear complex catalyst obtained by reacting a zinc carboxylate corresponding to a 3,3'-aminoiminobinaphthol ligand represented by the following formula (1). In the presence of , a styrene compound and a carboxylic acid are reacted to asymmetrically synthesize an optically active iodoester represented by the following formula (2), and the obtained iodoester is reacted with sodium azide.
なお、この結果、下記式（３）で示される光学活性アジドエステルを得ることができる。 Note that as a result, an optically active azide ester represented by the following formula (3) can be obtained.
なお上記式中、Ｒ１、Ｒ3は水素原子、アルキル基、アリール基、ハロゲン原子、アルコキシ基、又はカルボニル基、Ｒ2は水素原子、又はアルキル基である。 In the above formula, R 1 and R 3 are a hydrogen atom, an alkyl group, an aryl group, a halogen atom, an alkoxy group, or a carbonyl group, and R 2 is a hydrogen atom or an alkyl group.
以上、本発明により、光学活性ヨードエステルならびに光学活性アジドエステル及びその製造方法を提供することができる。光学活性アジドエステルからは、医薬の合成に有用な新規光学活性アミノアルコールを供給できるようになるほか、アジド官能基とアルキン分子の環化反応によりトリアゾール化合物を得る反応により、異種の生物活性化合物を連結したハイブリッド医薬の創製や、蛍光試薬と生物活性化合物の連結による医薬の可視化が可能になる。 As described above, the present invention can provide an optically active iodoester, an optically active azide ester, and a method for producing the same. Optically active azide esters can be used to supply new optically active amino alcohols that are useful for pharmaceutical synthesis, as well as to produce different biologically active compounds through the cyclization reaction between the azide functional group and alkyne molecules to obtain triazole compounds. It becomes possible to create linked hybrid drugs and to visualize drugs by linking fluorescent reagents and biologically active compounds.
以下、本発明の実施形態について図面を参照しつつ説明する。ただし、本発明は多くの異なる様態で実施することが可能であり、以下に示す実施形態に限定されるものではない。 Embodiments of the present invention will be described below with reference to the drawings. However, the invention can be implemented in many different ways and is not limited to the embodiments shown below.
（実施形態１）
本実施形態に係る光学活性ヨードエステルは、下記式（１）で示される３，３’－アミノイミノビナフトール配位子と亜鉛カルボキシレートからなる亜鉛二核錯体触媒の存在下で、スチレン化合物とカルボン酸を反応させることによって製造できる。尚、本配位子は、［特許文献１］ならびに［非特許文献３］記載の手法で合成できる。
(Embodiment 1)
The optically active iodoester according to the present embodiment is produced by combining a styrene compound and carbon dioxide in the presence of a zinc dinuclear complex catalyst consisting of a 3,3'-aminoiminobinaphthol ligand and zinc carboxylate represented by the following formula (1). It can be produced by reacting acids. In addition, this ligand can be synthesized by the method described in [Patent Document 1] and [Non-Patent Document 3].
具体的には、本実施形態に係る触媒の存在下で、下記式（４）で示される反応のように、スチレン化合物とカルボン酸を反応させてヨードエステルを合成することができる。 Specifically, in the presence of the catalyst according to the present embodiment, an iodoester can be synthesized by reacting a styrene compound and a carboxylic acid as in the reaction represented by the following formula (4).
上記反応は、非極性溶媒中、特にジクロロメタン中において行なうことが好ましい。 The above reaction is preferably carried out in a non-polar solvent, especially in dichloromethane.
上記反応は、マイナス７８度において行なうことが好ましい。ここで、上記式（４）に示す反応の最適化条件は、下記表１にまとめる実験によって得られた。 The above reaction is preferably carried out at minus 78 degrees. Here, the optimization conditions for the reaction shown in the above formula (4) were obtained through experiments summarized in Table 1 below.
ここにおいて限定されるわけではないがＲ１、Ｒ3は水素原子、アルキル基、アリール基、ハロゲン原子、アルコキシ基、又はカルボニル基、Ｒ2は水素原子、又はアルキル基を用いることができる。 Although not limited here, R 1 and R 3 can be a hydrogen atom, an alkyl group, an aryl group, a halogen atom, an alkoxy group, or a carbonyl group, and R 2 can be a hydrogen atom or an alkyl group.
ここで、限定されるわけではないが、アリール基の例として、フェニル基、１－ナフチル基、２－ナフチルなどを挙げることができ、アルキル基の例として、メチル基、エチル基などを挙げることができ、カルボニル基の例として、アセチル基、ベンゾイル基などを挙げることができる。 Here, examples of the aryl group include, but are not limited to, phenyl group, 1-naphthyl group, 2-naphthyl group, and examples of the alkyl group include methyl group, ethyl group, etc. Examples of the carbonyl group include an acetyl group and a benzoyl group.
なお、上記反応において、用いるカルボン酸の量は、スチレンを１モルとした場合、１．１モル以上１．９モル以下の範囲にあることが好ましく、より好ましくは１．１モル以上１．６モル以下の範囲内である。 In addition, in the above reaction, the amount of carboxylic acid used is preferably in the range of 1.1 mol or more and 1.9 mol or less, more preferably 1.1 mol or more and 1.6 mol or less, when styrene is 1 mol. It is within the range of mol or less.
この結果、本実施形態に係る方法によると、下記式（２）で示すヨードエステルを高い収率、立体選択性で得ることができる。 As a result, according to the method according to the present embodiment, the iodoester represented by the following formula (2) can be obtained with high yield and stereoselectivity.
光学活性アジドエステルは、上記式（２）で示されるヨードエステルに対し、アジ化ナトリウムを反応させることによって製造できる。 The optically active azide ester can be produced by reacting the iodoester represented by the above formula (2) with sodium azide.
具体的には、下記式（５）で示される反応のように、アジ化ナトリウムを反応させて光学活性アジドエステルを合成することができる。 Specifically, an optically active azide ester can be synthesized by reacting sodium azide as in the reaction shown by the following formula (5).
上記反応は、非プロトン性極性溶媒中、特にジメチルホルムアミド中において行なうことが好ましい。 The above reaction is preferably carried out in an aprotic polar solvent, particularly in dimethylformamide.
上記反応は、８０度において行なうことが好ましい。 The above reaction is preferably carried out at 80 degrees.
ここにおいて限定されるわけではないがＲ１、Ｒ3は水素原子、アルキル基、アリール基、ハロゲン原子、アルコキシ基、又はカルボニル基、Ｒ2は水素原子、又はアルキル基を用いることができる。 Although not limited here, R 1 and R 3 can be a hydrogen atom, an alkyl group, an aryl group, a halogen atom, an alkoxy group, or a carbonyl group, and R 2 can be a hydrogen atom or an alkyl group.
ここで、限定されるわけではないが、アリール基の例として、フェニル基、１－ナフチル基、２－ナフチルなどを挙げることができ、アルキル基の例として、メチル基、エチル基などを挙げることができ、カルボニル基の例として、アセチル基、ベンゾイル基などを挙げることができる。特に、Ｒ3は電子供与性置換基であるアルコキシ基を好適に用いることができる。 Here, examples of the aryl group include, but are not limited to, phenyl group, 1-naphthyl group, 2-naphthyl group, and examples of the alkyl group include methyl group, ethyl group, etc. Examples of the carbonyl group include an acetyl group and a benzoyl group. In particular, an alkoxy group, which is an electron-donating substituent, can be suitably used for R 3 .
なお、上記反応において、用いるアジ化ナトリウムの量は、ヨードエステルを１モルとした場合、１．０モル以上５．０モル以下の範囲にあることが好ましく、より好ましくは２．０モル以上４．０モル以下の範囲内である。 In the above reaction, the amount of sodium azide used is preferably in the range of 1.0 mol or more and 5.0 mol or less, more preferably 2.0 mol or more and 4.0 mol or less, based on 1 mol of iodoester. It is within the range of .0 mole or less.
この結果、本実施形態に係る方法によると、下記式（３）で示すアジドエステルを、光学純度を損なうことなく高い収率で得ることができる。 As a result, according to the method according to the present embodiment, the azide ester represented by the following formula (3) can be obtained in high yield without impairing optical purity.
以下、上記実施形態に係る触媒を用い、実際に光学活性アジドエステルを製造した。以下、具体的に説明する。 Hereinafter, an optically active azide ester was actually produced using the catalyst according to the above embodiment. This will be explained in detail below.
（実施例１）
下記式（６）に示す本実施例は、次のように行った。即ち、（Ｒ，Ｓ，Ｓ）３，３’－ビスアミノイミノビナフトール（０．０５ mmol）とパラメトキシ安息香酸亜鉛塩（０．０１０ mmol）を無水ジクロロメタン（４．０ ml）中で室温下１時間攪拌したのち、パラメトキシ安息香酸（０．１１ mmol）とα-メチルスチレン（０．１ mmol）を加えた。同反応容器を－７８ °Cに冷却し、３０分保冷後、N-ヨード-１，８-ナフタレンイミド (NIN)（０．１１ mmol） とヨウ素（０．０２ mmol）を加え反応を開始した。－７８ °Cにて２７時間反応させた後、反応液に飽和亜硫酸ナトリウム水溶液を加え反応を停止し、室温に戻した後、ジクロロメタンにより分液抽出を行った。有機相をボウ硝乾燥させた後、濃縮、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル=２０/１～１０/１）により精製することにより目的とするヨードエステル体を９９％化学収率で得た。
(Example 1)
The present example shown in formula (6) below was carried out as follows. That is, (R,S,S)3,3'-bisaminoiminobinaphthol (0.05 mmol) and paramethoxybenzoic acid zinc salt (0.010 mmol) were mixed in anhydrous dichloromethane (4.0 ml) at room temperature for 1 hour. After stirring for an hour, paramethoxybenzoic acid (0.11 mmol) and α-methylstyrene (0.1 mmol) were added. The reaction vessel was cooled to -78 °C and kept cold for 30 minutes, then N-iodo-1,8-naphthaleneimide (NIN) (0.11 mmol) and iodine (0.02 mmol) were added to start the reaction. . After reacting at -78 °C for 27 hours, a saturated aqueous sodium sulfite solution was added to the reaction solution to stop the reaction, and after returning to room temperature, liquid separation and extraction were performed with dichloromethane. After drying the organic phase, the desired iodoester was obtained in 99% chemical yield by concentrating and purifying the residue by silica gel column chromatography (hexane/ethyl acetate = 20/1 to 10/1). Obtained.
1H NMR (500 MHz, CDCl3) δ8.07-8.01 (m, 2H), 7.51-7.44 (m, 2H), 7.29-7.24 (m, 2H), 6.99-6.94 (m, 2H), 3.87 (s, 3H), 3.85 (d, J=11.0 Hz, 1H), 3.74 (d, J=10.5 Hz, 1H), 2.09 (s, 3H) 1 H NMR (500 MHz, CDCl 3 ) δ8.07-8.01 (m, 2H), 7.51-7.44 (m, 2H), 7.29-7.24 (m, 2H), 6.99-6.94 (m, 2H), 3.87 ( s, 3H), 3.85 (d, J=11.0 Hz, 1H), 3.74 (d, J=10.5 Hz, 1H), 2.09 (s, 3H)
13C NMR (125 MHz, CDCl3) δ164.6, 163.7, 141.1, 132.0, 131.8, 126.7, 123.0, 122.0, 113.9, 80.4, 55.6, 25.8, 17.5 13 C NMR (125 MHz, CDCl 3 ) δ164.6, 163.7, 141.1, 132.0, 131.8, 126.7, 123.0, 122.0, 113.9, 80.4, 55.6, 25.8, 17.5
HRMS calcd for C17H16O3BrINa (M+Na)+: 496.9220, found: m/z 496.9212 HRMS calcd for C 17 H 16 O 3 BrINa (M+Na) + : 496.9220, found: m/z 496.9212
IR (neat) 1710, 1604, 1285, 1252, 1156, 1097, 1078, 1026, 1007, 767 cm-1 IR (neat) 1710, 1604, 1285, 1252, 1156, 1097, 1078, 1026, 1007, 767 cm -1
[＜]D 23.4= -1.5 (c= 1.0, CHCl3, 85% ee) [＜] D 23.4 = -1.5 (c= 1.0, CHCl 3 , 85% ee)
得られたヨードエステル体の光学純度は、ダイセル社製Chiralpack AD-3カラムを用いた高速液体クロマトグラフィーにより決定し、その光学純度は８５％ eeであった（展開溶媒：ヘキサン／２－プロパノール＝７０／３０、流速：1.0 mL/min、検出波長：254 nm、保持時間：１２．４分、９．１分）。 The optical purity of the obtained iodoester was determined by high performance liquid chromatography using a Daicel Chiralpack AD-3 column, and the optical purity was 85% ee (developing solvent: hexane/2-propanol = 70/30, flow rate: 1.0 mL/min, detection wavelength: 254 nm, retention time: 12.4 minutes, 9.1 minutes).
（実施例２）
下記式（７）に示す本実施例は、次のように行った。即ち、上記式（６）の実施例によって得られたヨードエステル体（0.12 mmol, ８２% ee）をジメチルホルムアミド(DMF)（0.4 ml）に溶解し、アジ化ナトリウム（0.36 mmol）を０°Cで加えた。この反応液を８０°Cに加熱、１６時間攪拌した。反応液を再び０°Cに冷却し、水により希釈後、ジエチルエーテルで分液抽出を行った。有機相をボウ硝乾燥させた後、濃縮、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル=８／１）により精製することにより、目的とするアジドエステル体を７１％化学収率で得た。
(Example 2)
The present example shown in formula (7) below was carried out as follows. That is, the iodoester compound (0.12 mmol, 82% ee) obtained by the example of formula (6) above was dissolved in dimethylformamide (DMF) (0.4 ml), and sodium azide (0.36 mmol) was heated at 0 °C. I added it. This reaction solution was heated to 80°C and stirred for 16 hours. The reaction solution was cooled to 0°C again, diluted with water, and then subjected to liquid separation and extraction with diethyl ether. The organic phase was dried over sulfur salt, concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate = 8/1) to obtain the desired azide ester in a chemical yield of 71%.
1H NMR (400 MHz, CDCl3) δ 7.98-7.94 (m, 2H), 7.56-7.51 (m, 2H), 7.39-7.35 (m, 2H), 6.95-6.89 (m, 2H), 4.51 (d, J=12.0 Hz, 1H), 4.42 (d, J=11.6 Hz, 1H), 3.86 (s, 3H), 1.76 (s, 3H) 1 H NMR (400 MHz, CDCl 3 ) δ 7.98-7.94 (m, 2H), 7.56-7.51 (m, 2H), 7.39-7.35 (m, 2H), 6.95-6.89 (m, 2H), 4.51 (d , J=12.0 Hz, 1H), 4.42 (d, J=11.6 Hz, 1H), 3.86 (s, 3H), 1.76 (s, 3H)
13C NMR (100 MHz, CDCl3) δ165.8, 163.8, 139.6, 132.0, 127.8, 122.4, 121.8, 113.9, 70.5, 65.3, 55.6, 22.7 13 C NMR (100 MHz, CDCl 3 ) δ165.8, 163.8, 139.6, 132.0, 127.8, 122.4, 121.8, 113.9, 70.5, 65.3, 55.6, 22.7
HRMS calcd for C17H16O3N3BrNa (M+Na)+: 412.0267, found: m/z 412.0264 HRMS calcd for C 17 H 16 O 3 N 3 BrNa (M+Na) + : 412.0267, found: m/z 412.0264
[＜]D 25.6= +12.7 (c= 1.0, CHCl3, 84% ee) [＜] D 25.6 = +12.7 (c= 1.0, CHCl 3 , 84% ee)
IR (neat) 2108, 1713, 1604, 1165, 1092, 1027, 1007, 845, 821, 766 cm-1 IR (neat) 2108, 1713, 1604, 1165, 1092, 1027, 1007, 845, 821, 766 cm -1
得られたエステル体の光学純度は、ダイセル社製Chiralpack AD-3カラムを用いた高速液体クロマトグラフィーにより決定し、その光学純度は８２％ eeであった（展開溶媒：ヘキサン／２－プロパノール＝７０／３０、流速：1.0 mL/min、検出波長：254 nm、保持時間：６．６分、７．３分）。 The optical purity of the obtained ester was determined by high performance liquid chromatography using a Daicel Chiralpack AD-3 column, and the optical purity was 82% ee (developing solvent: hexane/2-propanol = 70% ee). /30, flow rate: 1.0 mL/min, detection wavelength: 254 nm, retention time: 6.6 minutes, 7.3 minutes).
以上の通り、本実施例によると、光学活性ジヒドロキノキサリノニル－スピロオキシインドール誘導体が高い収率と光学純度で合成できることを確認した。尚、上記式（７）に記載の光学活性アジドエステルを与える反応機構は、下記式（８）で示される。 As described above, according to this example, it was confirmed that an optically active dihydroquinoxalinonyl-spirooxindole derivative could be synthesized with high yield and optical purity. Incidentally, the reaction mechanism for producing the optically active azide ester described in the above formula (7) is shown by the following formula (8).
本発明は、過去に報告例のない光学活性アジドエステルを高い光学純度で供給できる。医薬・農薬の開発と生産に有用であり、産業上の利用可能性がある。 The present invention can supply an optically active azide ester with high optical purity, which has never been reported before. It is useful for the development and production of pharmaceuticals and agrochemicals, and has potential for industrial use.
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| JP2015038052A (en) | 2013-08-19 | 2015-02-26 | 国立大学法人 千葉大学 | Bisaminoimine ligand and catalyst having binaphthol skeleton |
| JP2016198736A (en) | 2015-04-12 | 2016-12-01 | 国立大学法人 千葉大学 | Catalyst having amino-salicylaldimine ligand coordinated to metal and method for producing iodine cyclized product using the same |
| WO2016202894A1 (en) | 2015-06-17 | 2016-12-22 | Universitaet Des Saarlandes | Method of converting alcohol to halide |
| JP2017206485A (en) | 2016-05-21 | 2017-11-24 | 国立大学法人 千葉大学 | Optically active 1,3-diamine derivative and method for producing the same |
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| JP2015038052A (en) | 2013-08-19 | 2015-02-26 | 国立大学法人 千葉大学 | Bisaminoimine ligand and catalyst having binaphthol skeleton |
| JP2016198736A (en) | 2015-04-12 | 2016-12-01 | 国立大学法人 千葉大学 | Catalyst having amino-salicylaldimine ligand coordinated to metal and method for producing iodine cyclized product using the same |
| WO2016202894A1 (en) | 2015-06-17 | 2016-12-22 | Universitaet Des Saarlandes | Method of converting alcohol to halide |
| JP2017206485A (en) | 2016-05-21 | 2017-11-24 | 国立大学法人 千葉大学 | Optically active 1,3-diamine derivative and method for producing the same |
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